Major histocompatibility complex class I-related protein A and B (MICA and MICB) are ligands for the natural killer group 2 member D (NKG2D) receptor and are widely expressed on tumor cells, with very limited expression on normal tissues.

Rheumatoid arthritis, atopic dermatitis, ulcerative colitis and several other inflammatory diseases involve hyperactivation of JAK-STAT signaling, in which the kinase JAK binds and phosphorylates the transcription factor STAT, which then turns on gene expression.

Tissue factor (TF), a transmembrane protein overexpressed in tumors such as cervical, head and neck, NSCLC, and pancreatic cancers, initiates the extrinsic coagulation pathway under normal subendothelial expression. TF-targeted vedotin antibody-drug conjugates (ADCs) are in clinical evaluation for solid tumors, but toxicities, including peripheral neuropathy, ocular effects and epistaxis, limit their use.

Tumors with high levels of microsatellite instability (MSI-H), such as some subsets of colorectal, endometrial and gastric cancers, are associated with a hypermutated phenotype and a specific dependency on the WRN gene. Pharmacologic inhibition of WRN has been shown to selectively impair the viability of MSI-H cancer cells, effectively blocking tumor growth while sparing microsatellite-stable (MSS) cells.

Interleukin-4 receptor α (IL-4Rα), a shared receptor subunit for both IL-4 and IL-13, along with thymic stromal lymphopoietin (TSLP), are key drivers of the type 2 inflammatory cascade involved in asthma and other inflammatory disorders.

Avenzo Therapeutics Inc. has announced IND clearance by the FDA for AVZO-1418 (DB-1418), an EGFR/HER3 bispecific antibody-drug conjugate (ADC). A first-in-human phase I/II study will begin later this year and will evaluate AVZO-1418 as a single agent and in combination therapy in patients with advanced solid tumors.